As intermediates of the aromatic amidine derivatives described in Japanese Patent Application Laid-Open (kokai) No. 5-208946, compounds of the following formulas (V), (Va), and (Vb), and salts thereof have conventionally been known: ##STR2##
[wherein R.sup.1 represents a protective group for a nitrogen atom and R.sup.3 represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms]; ##STR3##
[wherein R.sup.1 and R.sup.3 have the same meanings as described above]; and ##STR4##
[wherein R.sup.1 and R.sup.3 have the same meanings as described above]. Processes for preparing the above compounds are also described in the cited publication.
A typical process for preparing these intermediates comprises the following steps:
brominating 7-methyl-2-naphthalenecarbonitrile to thereby form 7-bromomethyl-2-naphthalenecarbonitrile (first step); PA1 further converting the 7-bromomethyl-2-naphthalenecarbonitrile to a phosphonium salt, [(7-cyano)-2-naphthyl)methyl]triphenylphosphonium bromide (second step); PA1 synthesizing ethyl 2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidinyl]oxy]phenyl]-2-ox oacetate using a Mitsunobu reaction of ethyl 2-(4-hydroxyphenyl)-2-oxoacetate and (3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine (third step); PA1 subjecting the obtained ethyl 2-[4-[[3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidinyl]oxy]phenyl]-2-oxo acetate and the [(7-cyano)-2-nahpthyl)methyl]-triphenylphosphonium bromide to a Wittig reaction (fourth step); PA1 further performing catalytic hydrogenation to thereby form compounds represented by formula (V) or (Va) (fifth step); and PA1 b 1) bromination in the first step is performed in tetrachloromethane, which is a suspected carcinogen; PA1 2) the product of the first step, i.e., 7-bromomethyl-2-naphthalenecarbonitrile, causes skin irritation when isolated as crystals; PA1 3) comparatively expensive reagents, diethyl azodicarboxylate and 1,8-diazabicyclo [5.4.0]-7-undecene, are used; PA1 4) by-products formed both in the third step and the fourth step behave as catalyst poisons in the catalytic hydrogenation of the fifth step, and in order to remove the by-products, it requires purification by silica gel column chromatography; PA1 5) palladium oxide monohydrate-barium sulfate, which is a catalyst of the catalytic hydrogenation, must be prepared upon use; and PA1 6) the yield of the sixth step is low and sodium hydride, which involves a safety problem, is used. PA1 that halogenation can be effectively performed in an alkylnitrile solvent in a first step, which permits the reaction to proceed to the next step without isolation of the product; PA1 that use of a pyrrolidinyloxyphenylacetic acid derivative, obtained through condensation of 4-hydroxyphenylacetic acids and sulfonyloxypyrrolidines, as one starting material provides a compound represented by formula (V) or (Va) without requiring reaction to form a phosphonium salt and catalytic hydrogenation, and further without need for preparation of an expensive reagent or a reagent required upon use; and PA1 that applying a base to a diasteromeric mixture of compounds represented by formula (Va) results in easy formation of compounds represented by formula (Vb). The present invention was accomplished based on these findings.
dissolving compounds represented by formula (Va) in ethanol with heat, adding a small amount of sodium hydride thereto, and causing crystallization while stirring the mixture at room temperature, to thereby obtain compounds represented by formula (Vb) (sixth step).
However, the above-described prior art process has the following drawbacks:
Briefly, the prior art process is unsatisfactory as an industrial process.
Accordingly, an object of the present invention is to provide an industrially satisfactory process for preparing compounds represented by formulas (V), (Va), and (Vb) and salts thereof, by use of safe, inexpensive, and easily available starting material(s) and auxiliary material(s) and without a silica gel chromatographic purification step, as well as to provide an industrial process for preparing intermediates of aromatic amidine derivatives which are described in Japanese Patent Application Laid-Open (kokai) No. 5-208946.